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CaMKII γ, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine
被引:89
|作者:
Gu, Ying
[1
,2
,3
]
Chen, Ting
[1
]
Meng, Zhipeng
[3
]
Gan, Yichao
[1
]
Xu, Xiaohua
[1
]
Lou, Guiyu
[3
]
Li, Hongzhi
[4
]
Gan, Xiaoxian
[5
]
Zhou, Hong
[1
]
Tang, Jinfen
[1
]
Xu, Genbo
[1
]
Huang, Liansheng
[1
]
Zhang, Xiaohong
[1
]
Fang, Yongming
[2
]
Wang, Kai
[2
]
Zheng, Shu
[2
]
Huang, Wendong
[3
]
Xu, Rongzhen
[1
,2
]
机构:
[1] China Natl Minist Educ, Dept Hematol, Key Lab Canc Prevent & Intervent, Hangzhou, Zhejiang, Peoples R China
[2] Zhejiang Univ, Inst Canc, Sch Med, Affiliated Hosp 2, Hangzhou 310009, Zhejiang, Peoples R China
[3] City Hope Natl Med Ctr, Beckman Res Inst, Div Gene Regulat & Drug Discovery, Duarte, CA 91010 USA
[4] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Med, Duarte, CA 91010 USA
[5] Zhejiang Acad Med Sci, Hangzhou, Zhejiang, Peoples R China
来源:
基金:
中国国家自然科学基金;
关键词:
CHRONIC MYELOID-LEUKEMIA;
FACTOR-KAPPA-B;
PROTEIN-KINASE-II;
BCR-ABL;
STEM-CELLS;
ANTILEUKEMIA ACTIVITY;
CALMODULIN;
APOPTOSIS;
INHIBITION;
PATHWAY;
D O I:
10.1182/blood-2012-06-434894
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
Bcr-Abl tyrosine kinase inhibitors (TKIs) have been a remarkable success for the treatment of Ph+ chronic myeloid leukemia (CML). However, a significant proportion of patients treated with TKIs develop resistance because of leukemia stem cells (LSCs) and T315I mutant Bcr-Abl. Here we describe the unknown activity of the natural product berbamine that efficiently eradicates LSCs and T315I mutant Bcr-Abl clones. Unexpectedly, we identify CaMKII gamma as a specific and critical target of berbamine for its antileukemia activity. Berbamine specifically binds to the ATP-binding pocket of CaMKII gamma, inhibits its phosphorylation and triggers apoptosis of leukemia cells. More importantly, CaMKII gamma is highly activated in LSCs but not in normal hematopoietic stem cells and coactivates LSC-related beta-catenin and Stat3 signaling networks. The identification of CaMKII gamma as a specific target of berbamine and as a critical molecular switch regulating multiple LSC-related signaling pathways can explain the unique antileukemia activity of berbamine. These findings also suggest that berbamine may be the first ATP-competitive inhibitor of CaMKII gamma, and potentially, can serve as a new type of molecular targeted agent through inhibition of the CaMKII gamma activity for treatment of leukemia. (Blood. 2012;120(24):4829-4839)
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页码:4829 / 4839
页数:11
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